CD8+ T cell metabolic flexibility elicited by CD28-ARS2 axis-driven alternative splicing of PKM supports antitumor immunity.

Autor: Holling GA; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.; University of Colorado Boulder, Boulder, CO, 80309, USA., Chavel CA; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA., Sharda AP; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA., Lieberman MM; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA., James CM; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA., Lightman SM; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA., Tong JH; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA., Qiao G; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.; Dana Farber Cancer Institute, Boston, MA, 02215, USA., Emmons TR; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.; Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.; Massachusetts Institute of Technology, Boston, MA, 02139, USA., Giridharan T; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.; Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA., Hou S; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Intlekofer AM; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Higashi RM; Center for Environmental Systems Biochemistry, Department of Toxicology and Cancer Biology and Markey Cancer Center, Lexington, KY, 40536, USA., Fan TWM; Center for Environmental Systems Biochemistry, Department of Toxicology and Cancer Biology and Markey Cancer Center, Lexington, KY, 40536, USA., Lane AN; Center for Environmental Systems Biochemistry, Department of Toxicology and Cancer Biology and Markey Cancer Center, Lexington, KY, 40536, USA., Eng KH; Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA., Segal BH; Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA., Repasky EA; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA., Lee KP; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.; Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.; Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA., Olejniczak SH; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA. scott.olejniczak@roswellpark.org.
Jazyk: angličtina
Zdroj: Cellular & molecular immunology [Cell Mol Immunol] 2024 Mar; Vol. 21 (3), pp. 260-274. Date of Electronic Publication: 2024 Jan 18.
DOI: 10.1038/s41423-024-01124-2
Abstrakt: Metabolic flexibility has emerged as a critical determinant of CD8+ T-cell antitumor activity, yet the mechanisms driving the metabolic flexibility of T cells have not been determined. In this study, we investigated the influence of the nuclear cap-binding complex (CBC) adaptor protein ARS2 on mature T cells. In doing so, we discovered a novel signaling axis that endows activated CD8+ T cells with flexibility of glucose catabolism. ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events. Among these effects, the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2, a key determinant of CD8+ T-cell glucose utilization, interferon gamma production, and antitumor effector function. Importantly, PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation, revealing a novel means by which costimulation reprograms glucose metabolism in CD8+ T cells.
(© 2024. The Author(s).)
Databáze: MEDLINE
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